Why do patients with hypopituitarism still present an increased mortality?

Hypopituitarism is defined as a lack or decreased secretion of one or several pituitary hormones. It can result from diseases of the pituitary gland or from pathologies of the superior regulatory center, i.e. the hypothalamus, thereby decreasing hypothalamic releasing hormones and consequently the pituitary hormones. It is still a rare disease with an estimated prevalence of 30-45 patients/100,000 and an incidence of 4-5/100,000/year. This review summarizes the currently available data with a focus on etiologies of hypopituitarism, evidence on mortality rates in patients with hypopituitarism, temporal trends in mortality , and associated diseases, pathophysiological mechanisms and risk factors that affect mortality risk in these patients.

Inflammatory Factor Levels and Clinical Characteristics of Mental Disorders in Patients with Sheehan Syndrome.

Background: Sheehan's syndrome often occurs in women aged 20 to 40 years. Bleeding is the main cause of the disease. This syndrome is rarely reported in the literature either in China or abroad, and it is rare in psychiatric clinic. Objective: To investigate the inflammatory factors levels and clinical characteristics of mental disorders in patients with Sheehan's syndrome in order to improve rational clinical diagnosis and treatment and reduce the occurrence of mental disorders. Design: This was a retrospective study. Setting: This study was performed in the Department of Endocrinology of Xingtai People' s Hospital in China. Participants: A total of 100 patients with Sheehan's syndrome admitted to Xingtai People's Hospital, China, from 2016 to 2021 were included in the study. According to the occurrence of mental disorders during treatment, they were divided into the psychological disorder group (PS group), psychological disorder during treatment group (TPS group) and non-psychological disorder group (NPS group). Methods: The clinical data of the 3 groups were retrospectively analyzed to explore the levels of inflammatory factors and clinical characteristics of mental disorders in patients with Sheehan's syndrome. Results: In the PS group, compared with the other 2 groups, onset to diagnosis time was longer (P < .05). There was a statistical difference in systolic blood pressure (SBP) among the 3 groups. The SBP in the PS group was the lowest, and that in the TPS group was higher than in the PS group and lower than in the NPS group (P < .05). Compared with TPS group, in the PS group the diastolic blood pressure (DBP), blood sodium, blood glucose, free triiodothyronine (FT3), free thyroxine (FT4), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were not significantly different, but were lower than in the NPS group (P < .05). There was no significant difference in age, disease course, body mass index (BMI), thyroid-stimulating hormone (TSH), cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), Prolactin (PRL), follicle-stimulating hormone( FSH), luteinizing hormone (LH ) and estradiol (E2) in the 3 groups. In the treatment process, the amount of hydrocortisone administered on the first, second day, and third day and the first 3 days in the TPS group were significantly higher than in the NPS group, and the increased rate of serum sodium on the first day in the TPS group was significantly higher than in the NPS (P < .05). Conclusion: Mental health illnesss are more likely to occur in patients with Sheehan's syndrome who are not diagnosed in time for various reasons, in patients with obvious anterior pituitary dysfunction, and in patients with high levels of inflammatory factors, large doses of glucocorticoid at the early stage of the disease and rapid increase of serum sodium at the first day of treatment.

Hypothalamitis and pituitary atrophy.

Hypothalamitis is a rare inflammatory disorder involving the hypothalamus and classified as primary, or isolated, and secondary hypothalamitis. Secondary hypothalamitis although very rare is more common than the primary one and may occur in patients affected by autoimmune diseases such as autoimmune hypophysitis, systemic autoimmune diseases, infective diseases in patients affected by immune-deficit, paraneoplastic encephalitis, or in patients treated with immune checkpoint inhibitors. In accordance with the rarity of this disease, diagnosis and management of hypothalamitis prove to be challenging. The diagnosis requires a high index of clinical suspicion. The main symptoms may be: various degrees of hypopituitarism, neuropsychiatric and behavioral disorders, and disturbances of autonomic and metabolic regulation. Magnetic resonance images play a crucial role in the diagnosis of hypothalamitis and in the exclusion of a neoplastic lesion. Therapeutic management should be oriented according to the disease etiology. In most cases, after ruling out infective hypothalamitis, the mainstay of therapy consists of immunosuppressive treatment. Great attention should be paid to hormonal replacement therapy, if partial or total hypopituitarism is present, in particular in patients affected by diabetes insipidus, central hypoadrenalism and hypothyroidism. According to the complexity of this disease, a multidisciplinary approach is strongly advocated to reach an early diagnosis and an integrated therapy.

Antibodies against the pituitary and hypothalamus in boxers.

Traumatic brain injury (TBI), a growing public health problem worldwide, has recently been recognized as one of the leading causes of hypopituitarism. The main causes of TBI-induced pituitary dysfunction are car accidents, falls, violence, sports-related brain injury, and war accidents, including blast-related brain injuries. Car accidents and falls are the most common causes of TBI and pituitary dysfunction among the younger generation and elderly population, respectively. The prevalence of hypopituitarism after TBI is about 30%. GH is the most common hormone lost. The mechanisms underlying hypopituitarism are still unclear; however, recent studies have demonstrated that hypoxic insult, increased intracranial pressure, axonal injury, genetic predisposition, neuroinflammation, and autoimmunity may be responsible for the development of pituitary dysfunction. Neuroendocrine abnormalities are recently described in athletes dealing with contact sports, including boxing and kickboxing, which are characterized by chronic repetitive head trauma. Mild TBI and concussion are accepted in boxing and kickboxing. The positivity of antipituitary and antihypothalamic antibodies is also a significant risk factor in the development of neuroendocrine abnormalities. Autoimmune reaction may also be responsible for the reduction in pituitary volume in boxers with hypopituitarism. In this chapter, the role of autoimmunity in the occurrence of pituitary dysfunction among boxers is discussed.

Occurrence of pituitary hormone deficits in relation to both pituitary and hypothalamic doses after radiotherapy for skull base meningioma.

CONTEXT: Little accurate information is available regarding the risk of hypopituitarism after irradiation of skull base meningiomas. DESIGN: Retrospective study in a single centre. PATIENTS: 48 patients with a skull base meningioma and normal pituitary function at diagnosis, treated with radiotherapy (RXT) between 1998 and 2017 (median follow-up of 90 months). MEASUREMENTS: The GH, TSH, LH/FSH and ACTH hormonal axes were evaluated yearly for the entire follow-up period. Mean doses delivered to the pituitary gland (PitD) and the hypothalamus (HypoD) were calculated, as well as the doses responsible for the development of deficits in 50% of patients after 5 years (TD50). RESULTS: At least one hormone deficit was observed in 38% of irradiated patients and complete hypopituitarism in 13%. The GH (35%), TSH (32%) and LH/FSH axes (28%) were the most frequently affected, while ACTH secretion axis was less altered (13%). The risk of hypopituitarism was independently related to planning target volume (PTV) and to the PitD (threshold dose 45 Gy; TD50 between 50 and 54 Gy). In this series, the risk was less influenced by the HypoD, increasing steadily between doses of 15 and 70 Gy with no clear-cut dose threshold. CONCLUSIONS: Over a median follow-up period of 7.5 years, hypopituitarism occurred in more than one third of patients irradiated for a skull base meningioma, and this prevalence was time- and dose-dependent. In this setting, the risk of developing hypopituitarism was mainly determined by the irradiated target volume and by the dose delivered to the pituitary gland.

Effect of Traditional Chinese Medicine on Long-Term Outcomes of Snakebite in Taiwan.

Herein, we review the characteristics of the six predominant venomous snakes in Taiwan and the effects of traditional Chinese medicine on the long-term outcomes of snakebite venom. We electronically searched databases, including PubMed, ClinicalKey, China National Knowledge Infrastructure, National Digital Library of Theses and Dissertations in Taiwan, and Airiti Library, from their inception to November 2019 by using the following Medical Subject Headings' keywords: snakebite, long-term, chronic, Chinese medicine, CAM, herb, and Taiwan. The most common long-term effects of snakebite envenomation include "migraine-like syndrome", brain injuries caused by hypoxia or intracranial hemorrhage, and chronic kidney disease. In addition, hypopituitarism is also worth mentioning. Traditional Chinese medicine can potentially be used in a complementary or alternative treatment for these effects, but additional studies are needed.

Are hypothalamic- pituitary (HP) axis deficiencies after whole brain radiotherapy (WBRT) of relevance for adult cancer patients? - a systematic review of the literature.

BACKGROUND: Cranial radiotherapy (cRT) can induce hormonal deficiencies as a consequence of significant doses to the hypothalamic-pituitary (HP) axis. In contrast to profound endocrinological follow-up data from survivors of childhood cancer treated with cRT, little knowledge exists for adult cancer patients. METHODS: A systematic search of the literature was conducted using the PubMed database and the Cochrane library offering the basis for our debate of the relevance of HP axis impairment after cRT in adult cancer patients. Against the background of potential relevance for patients receiving whole brain radiotherapy (WBRT), a particular focus was set on the temporal onset of hypopituitarism and the radiation dose to the HP axis. RESULTS: Twenty-eight original papers with a total of 1728 patients met the inclusion criteria. Radiation doses to the HP area ranged from 4 to 97 Gray (Gy). Hypopituitarism incidences ranged from 20 to 93% for adult patients with nasopharyngeal cancer or non-pituitary brain tumors. No study focused particularly on hypopituitarism after WBRT. The onset of hypopituitarism occurred as early as within the first year following cRT (range: 3 months to 25.6 years). However, since most studies started follow-up evaluation only several years after cRT, early onset of hypopituitarism might have gone unnoticed. CONCLUSION: Hypopituitarism occurs frequently after cRT in adult cancer patients. Despite the general conception that it develops only after several years, onset of endocrine sequelae can occur within the first year after cRT without a clear threshold. This finding is worth debating particularly in respect of treatment options for patients with brain metastases and favorable survival prognoses.

Preservation of Hypothalamic Function with Endoscopic Endonasal Resection of Hypothalamus-Invaded Craniopharyngiomas.

OBJECTIVE: To analyze the preservation of hypothalamic function using the endoscopic endonasal approach (EEA) in a single-center clinical series of patients with hypothalamus-invaded craniopharyngioma (CP) and compare this series with reported cases by the open transcranial approach (TCA). METHODS: A retrospective review of hypothalamus-invaded CP surgical cases treated with EEA was performed. Hypothalamic damage was evaluated in terms of the body mass index (BMI), endocrine status, and quality of life before and after surgery. A review of the available literature reporting the use of EEA and TCA over the last decade was performed for comparison. RESULTS: In total, 63 cases amenable to EEA were investigated. The elevation in BMI was substantial and an increase in BMI greater than 9% was observed in 22 patients (34.92%). Most patients exhibited a BMI gain >9% within 3 months postoperatively. A total of 16 of the 19 patients who had normal anterior pituitary function preoperatively worsened after surgery. Of the 27 cases reporting preoperative partial hypopituitarism, 16 cases worsened postoperatively and 11 cases remained unchanged. All 9 cases with preoperative panhypopituitarism remained unchanged postoperatively. A total of 40 new cases developed diabetes insipidus, and 3 of the 10 patients with preoperative diabetes insipidus exhibited resolved at the latest follow-up. The quality of life showed no significant difference. CONCLUSIONS: EEA can achieve greater gross total resection than TCA when performed by an experienced surgeon. Combined with the reduced postoperative hypothalamic damage in our patients with only hypothalamus-invaded CP, especially the shortened time horizons of hypothalamic obesity development and reduced percentage of patients with obesity, the EEA technique should be a preferred alternative over TCA.

Major Issues of Care in Thalassemia Major Children Refugees.

Beta thalassemia major (ßTM) is the most common inherited hemoglobinopathy. Management essentially focuses on preventing and treating complications. Conventional treatment is based on a regular blood transfusion program, and chelation therapy. Management essentially focuses on preventing and treating complications. Severe complications of ßTM are very rarely seen in children in Europe. In the context of the migrant crisis, pediatricians will be confronted with the challenge of managing severe complicated ßTM. We report the case of 2 Syrian 10-year-old twin girls who arrived to France with numerous and severe complications of ßTM: hemochromatosis, alloimmunization, hypopituitarism, osteopenia… Their clinical management, which led to successful vital and functional improvement, is reported in this article.

Hypoxic stress: A risk factor for post-concussive hypopituitarism?

Hypopituitarism diagnosed months or years following concussive injury can cause a variety of endocrine disturbances including insufficient secretion of human growth, luteinizing, follicle stimulating, thyroid stimulating, adrenocorticotrophic, and antidiuretic hormones. Recent evidence suggests that autoimmune reactions against pituitary and/or hypothalamic tissue constitute an etiologic factor for this hypopituitarism. One important trigger for autoimmunity is hypoxic stress. This trigger may be especially important in the post-concussive brain, which is particularly vulnerable to hypoxic stress. The vulnerable vasculature of the hypothalamic infundibulum can be a source of local exacerbation of any systemic hypoxia. Taking the above into account, it seems reasonable to hypothesize that hypoxic stress is a risk factor for post-concussive hypopituitarism. Following a discussion of literature relevant to this hypothesis, we suggest retrospective and prospective research methods for testing the hypothesis. Retrospective methods for hypothesis testing include comparing post-concussion victims with and without evidence of hypopituitarism in terms of their history of respiratory problems such as smoking, exposure to indoor and outdoor air pollution, chronic obstructive pulmonary disease, asthma, obstructive sleep apnea, and opioid use or abuse. Significantly greater incidence of respiratory history among the hypopituitarism patients would support the hypothesis. Prospective methods include performing detailed respiratory history and examination immediately post-injury, then performing periodic endocrine panels to detect hypopituitarism during long-term follow up. The hypothesis will be supported if development of hypopituitarism among patients with positive respiratory history or examination findings post-injury is more frequent than hypopituitarism among concussion victims with negative respiratory history and exam findings. If the hypothesis is supported, effective prevention of post-concussive hypopituitarism should include efforts to support optimal respiratory function. Such efforts may be relevant to treatment as well. These efforts would include respiratory therapy, smoking cessation, treatment of obstructive sleep apnea, prudent stepping down of opioid use, incentive spirometry, aerobic exercise, and other conventional measures as indicated. Non-Western measures such as yoga should be considered as well. In addition, chiropractic care as an intervention that may ameliorate hypoxia at the systemic and local levels is discussed.

Hypothalamic hypopituitarism secondary to suprasellar metastases from small cell lung cancer: a case report and review of the literature.

BACKGROUND: Metastasis to the pituitary gland is an infrequent clinical problem, and the symptoms caused by metastases have been reported in only 2.5-18.2% of the cases. However, metastasis to the suprasellar lesion has rarely been reported in the literature. To the best of our knowledge, only nine cases of hypothalamic hypopituitarism due to metastases of solid tumors have been reported in English-language journals. CASE PRESENTATION: A 67-year-old Japanese man presented to our hospital with generalized weakness, lethargy, and weight loss. Laboratory data showed hypoglycemia together with low thyroid-stimulating hormone and free thyroxine. We suspected hypopituitarism and performed imaging of the head, which revealed multiple tumors, one of which was in the suprasellar region. Computed tomography of the chest showed a tumor shadow, and a bronchoscopic biopsy pathologically showed small cell lung cancer. Hormone profiling demonstrated hypothalamic pan-hypopituitarism. We diagnosed hypothalamic hypopituitarism secondary to metastases from the primary lung cancer and initiated radiation, chemotherapy, and hormone replacement, but the patient died 10 months later. CONCLUSIONS: We report a case of a 67-year-old man with hypothalamic hypopituitarism secondary to a suprasellar metastasis from a primary small cell lung cancer, and we review ten cases of hypothalamic hypopituitarism due to metastases, including our patient. Recognizing hypopituitarism can be challenging, especially in the elderly, whose symptoms such as lethargy and visual decline may be mistaken for the natural aging process. In patients with established metastatic conditions, the symptoms may be wrongly attributed to malignancy or to the side effects of therapy. When a patient is suspected of having hypopituitarism, a hormone load test can help to diagnose the type of hypopituitarism. It is important to evaluate the brain and the whole body to confirm whether metastasis and primary cancer exist. Because the mortality rate is very high, aggressive intervention for both diagnosis and therapy is required in cases of hypothalamic hypopituitarism secondary to tumor metastasis.

Hypothalamic demyelination causing panhypopituitarism.

Hypothalamic involvement in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is rare and endocrinopathies involving the hypothalamic-pituitary axis in patients with demyelinating conditions have rarely been reported. We present two cases of MS/NMOSD with associated hypothalamic-pituitary involvement and subsequent hypopituitarism, including the first report of a patient with hypothalamic demyelination causing panhypopituitarism. Differential diagnoses, including alemtuzumab-related and primary pituitary pathology are discussed.

Four-year follow-up of a Wilson disease pedigree complicated with epilepsy and hypopituitarism: Case report with a literature review.

RATIONALE: Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism with excellent prognosis if treated timely. However, WD is usually prone to neglect and misdiagnosis at an early stage. We reported a rare WD pedigree, and the clinical features, laboratory tests, and gene mutations were analyzed in detail. PATIENT CONCERNS: The patient was a 17-year-old and 136-cm-tall girl who presented with limb weakness, combined with multi-organ disorders including blind eye, epilepsy, and hypopituitarism. DIAGNOSES: Clinical tests showed a low serum ceruloplasmin level, high urinary copper excretion and Kayser-Fleischer (K-F) rings. She carried a compound heterozygous mutations in ATP7B gene (c.2828G>A and c.3884C>T). Her younger brother, as an asymptomatic patient, manifested with elevation of transaminases but without neurological and hepatic symptoms. They were diagnosed as WD finally. INTERVENTIONS: They were treated with sodium dimercaptosulphonate, supplemented with zinc gluconate, vitamin B6, vitamin C, as well as restriction of dietary copper. OUTCOMES: The urinary copper excretion and serum transaminase level decreased gradually. The abnormal signals in brainstem and basal ganglia were also remarkably decreased after 4-year of de-copper treatment. LESSONS: As to the patients with complicated clinical manifestations, the extrapyramidal symptom and basal ganglia signals should be concerned. The serum ceruloplasmin detection and ATP7B gene mutation screening are necessary.

Hypopituitarism in the elderly: a narrative review on clinical management of hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes dysfunction.

Hypopituitarism is an uncommon and under-investigated endocrine disorder in old age since signs and symptoms are unspecific and, at least in part, can be attributed to the physiological effects of aging and related co-morbidities. Clinical presentation is often insidious being characterized by non-specific manifestations, such as weight gain, fatigue, low muscle strength, bradipsychism, hypotension or intolerance to cold. In these circumstances, hypopituitarism is a rarely life-threatening condition, but evolution may be more dramatic as a result of pituitary apoplexy, or when a serious condition of adrenal insufficiency suddenly occurs. Clinical presentation depends on the effects that each pituitary deficit can cause, and on their mutual relationship, but also, inevitably, it depends on the severity and duration of the deficit itself, as well as on the general condition of the patient. Indeed, indications and methods of hormone replacement therapy must include the need to normalize the endocrine profile without contributing to the worsening of intercurrent diseases, such as those of glucose and bone metabolism, and the cardiovascular system, or to the increasing cancer risk. Hormonal requirements of elderly patients are reduced compared to young adults, but a prompt diagnosis and appropriate treatment of pituitary deficiencies are strongly recommended, also in this age range.

Hypothalamic-pituitary sarcoidosis with vision loss and hypopituitarism: case series and literature review.

PURPOSE: Hypothalamic-pituitary (HP) neurosarcoidosis (NS) accounts for 0.5 % cases of sarcoidosis and 1 % of HP masses. Correlative data on endocrine and neurological outcomes is lacking. METHODS: Retrospective case series and literature review of presentation, treatment and outcome of HP NS. RESULTS: Our series includes 4 men, ages 34-59, followed for a median of 7.3 years (range 1.5-17). All had optic neuropathy, multiple pituitary hormone abnormalities (PHAs) and other organ involvement by sarcoidosis (lung, sino-nasal, brain/spine and facial nerve). Two patients had central diabetes insipidus and one impaired thirst with polydipsia. After treatment with high-dose glucocorticoids, optic neuropathy improved in one case and stabilized in the others. After treatment, HP lesions improved radiologically, but PHAs persisted in all cases. Review of four published series on HP NS in addition to ours yielded 46 patients, age 37 ± 11.8 years, 65 % male. PHAs consisted of anterior hypopituitarism (LH/FSH 88.8 %, TSH 67.4 %, GH 50.0 %, ACTH 48.8 %), hyperprolactinemia (48.8 %) and diabetes insipidus (65.2 %). PHAs were the first sign of disease in 54.3 % patients. Vision problems occurred in 28.3 % patients, but optic neuropathy was not well documented in previous series. Most patients (93.5 %) received high-dose glucocorticoids followed by taper; 50 % also received other immunomodulators, including methotrexate, mycophenolate mofetil, cyclosporine, azathioprine, infliximab and hydrochloroquine. Only 13 % patients showed improvement in PHAs. All-cause mortality was 8.7 %. CONCLUSION: HP NS is a serious disease requiring multidisciplinary treatment and lifelong follow-up. Prospective multicentric studies are needed to determine a more standardized approach to HP NS and outline predictors of disease outcome.

Alternative causes of hypopituitarism: traumatic brain injury, cranial irradiation, and infections.

Hypopituitarism often remains unrecognized due to subtle clinical manifestations. Anterior pituitary hormone deficiencies may present as isolated or multiple and may be transient or permanent. Traumatic brain injury (TBI) is recognized as a risk factor for hypopituitarism, most frequently presenting with isolated growth hormone deficiency (GHD). Data analysis shows that about 15% of patients with TBI have some degree of hypopituitarism which if not recognized may be mistakenly ascribed to persistent neurologic injury and cognitive impairment. Identification of predictors for hypopituitarism after TBI is important, one of them being the severity of TBI. The mechanisms involve lesions in the hypothalamic-pituitary axis and inflammatory changes in the central nervous system (CNS). With time, hypopituitarism after TBI may progress or reverse. Cranial irradiation is another important risk factor for hypopituitarism. Deficiencies in anterior pituitary hormone secretion (partial or complete) occur following radiation damage to the hypothalamic-pituitary region, the severity and frequency of which correlate with the total radiation dose delivered to the region and the length of follow-up. These radiation-induced hormone deficiencies are irreversible and progressive. Despite numerous case reports, the incidence of hypothalamic-pituitary dysfunction following infectious diseases of the CNS has been underestimated. Hypopituitarism usually relates to the severity of the disease, type of causative agent (bacterial, TBC, fungal, or viral) and primary localization of the infection. Unrecognized hypopituitarism may be misdiagnosed as postencephalitic syndrome, while the presence of a sellar mass with suprasellar extension may be misdiagnosed as pituitary macroadenoma in a patient with pituitary abscess which is potentially a life-threatening disease.

Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice.

Traumatic brain injury is a leading cause of hypopituitarism, which compromises patients' recovery, quality of life, and life span. To date, there are no means other than standardized animal studies to provide insights into the mechanisms of posttraumatic hypopituitarism. We have found that GH levels were impaired after inducing a controlled cortical impact (CCI) in mice. Furthermore, GHRH stimulation enhanced GH to lower level in injured than in control or sham mice. Because many characteristics were unchanged in the pituitary glands of CCI mice, we looked for changes at the hypothalamic level. Hypertrophied astrocytes were seen both within the arcuate nucleus and the median eminence, two pivotal structures of the GH axis, spatially remote to the injury site. In the arcuate nucleus, GHRH neurons were unaltered. In the median eminence, injured mice exhibited unexpected alterations. First, the distributions of claudin-1 and zonula occludens-1 between tanycytes were disorganized, suggesting tight junction disruptions. Second, endogenous IgG was increased in the vicinity of the third ventricle, suggesting abnormal barrier properties after CCI. Third, intracerebroventricular injection of a fluorescent-dextran derivative highly stained the hypothalamic parenchyma only after CCI, demonstrating an increased permeability of the third ventricle edges. This alteration of the third ventricle might jeopardize the communication between the hypothalamus and the pituitary gland. In conclusion, the phenotype of CCI mice had similarities to the posttraumatic hypopituitarism seen in humans with intact pituitary gland and pituitary stalk. It is the first report of a pathological status in which tanycyte dysfunctions appear as a major acquired syndrome.